Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis

• Safety [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Safety and tolerability of adjunctive sertraline (grade 4-5) adverse reactions)
• Intolerance [ Time Frame: 12 weeks ] [ Designated as safety issue: Yes ]
  Time to dose-reduction for intolerance
• Survival [ Time Frame: 10 weeks ] [ Designated as safety issue: Yes ]
  10-week survival time
• Microbiologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  2 week CSF culture sterility
• Neurocognitive Performance [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Quantitative neurocognitive performance score (QNPZ-8) and Center for Epidemiologic Studies in Depression (CES-D) scale at 4 and 12 weeks.

This is a phase I/II trial to determine whether adjunctive sertraline will lead to a faster rate of fungal clearance of Cryptococcus neoformans from cerebrospinal fluid (CSF), as measured by early fungicidal activity (EFA), compared to standard therapy alone.

This is a phase I/II randomized trial to evaluate the early fungicidal activity (EFA) of sertraline when added to standard amphotericin-based therapy for cryptococcal meningitis, with the hypothesis that adjunctive sertraline will lead to faster fungal clearance. Cryptococcal meningitis diagnosis will be made via CSF cryptococcal antigen (CRAG) at time of lumbar puncture (LP) with confirmation by CSF culture. After informed consent, subjects that meet eligibility requirements will be able to enter study. A non-randomized phase I dose-escalation study will first be conducted to help optimize dosing for a larger randomized phase II study.

Phase I Design: In addition to standard induction therapy for cryptococcal meningitis, subjects will receive increasing doses of sertraline in a dose-escalation study design. The first subjects enrolled into the study will receive 100 mg/day of sertraline. This dose will be sequentially increased by 100 mg/day in groups of n=5 up to a maximum of 400mg daily. Total anticipated enrollment: 20 subjects.

Phase II Design: Subjects will be randomized to standard induction therapy with masked placebo or sertraline at two different doses to be determined in Phase I of the trial. We will use a permutated block randomization in a 1:1:1 allocation (n=40 per arm). Total anticipated enrollment: 120 subjects.

• Cryptococcal Meningitis
• Fungal Meningitis

• Placebo Comparator: Placebo
  Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day).
• Experimental: Sertraline Dose 1
  Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy. Phase II dose to be determined in phase I trial.
  Intervention: Drug: Sertraline
• Experimental: Sertraline Dose 2
  Standard cryptococcal meningitis therapy with amphotericin (0.7-1.0 mg/kg/day) + fluconazole (800-1200mg/day plus adjunctive sertraline therapy. Phase II dose to be determined in phase I trial.
  Intervention: Drug: Sertraline

Inclusion Criteria:

• Cryptococcal meningitis diagnosed by either:

  1. CSF cryptococcal culture
  2. CSF cryptococcal antigen (CRAG)
• Receiving amphotericin-based anti-fungal therapy
• HIV-1 infection
• Ability and willingness of the participant or legal guardian/representative to provide informed consent

Exclusion Criteria:

• Age < 18 years
• History of prior ART use (Phase I only)
• Receipt of >3 doses of amphotericin therapy
• Cannot or unlikely to attend regular clinic visits
• History of known liver cirrhosis
• Presence of jaundice
• Pregnancy
• Current breastfeeding